At the 16-cell stage of mammalian preimplantation development, pluripotent cells that give rise to all embryonic tissues are established at the same time as extra-embryonic lineages, such as those contributing to the placenta. A key protein that distinguishes pluripotent cells from their differentiating neighbours is the transcription factor SOX2. Here, Amy Ralston and colleagues investigate how the expression of Sox2 in early mouse embryos is regulated. They show that the core pluripotency factors NANOG and OCT4 are not required for Sox2 expression at the 16- and 32-cell stages, but act to maintain SOX2 levels at later stages of development. They also demonstrate that timely Sox2 expression is regulated by TEAD4 and its co-factors WWTR1 and YAP1, which repress Sox2 transcription prior to the 16-cell stage. Injection of mRNA encoding LATS2, a component of the Hippo pathway, into 2-cell embryos promotes premature Sox2 expression, indicating that Hippo signalling negatively regulates the nuclear activity of TEAD4/WWTR1/YAP1. Furthermore, TEAD4/WWTR1/YAP1 likely repress Sox2 by directly binding to the Sox2 locus, as fusion of a transcriptional activator to TEAD4 induces precocious Sox2 expression. Together, these findings suggest that regulation of Sox2 by the Hippo pathway is key to establishing pluripotency in early mammalian development.

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